‘… The End of the Beginning’: Cdk1 Thresholds and Exit from Mitosis

Wolf, Frank de; Sigl, Reinhard; Geley, Stephan

doi:10.4161/cc.6.12.4361

Cited by 42 publications

(39 citation statements)

References 39 publications

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“…Based on these observations, we speculated that fate after mitotic arrest may depend on the robustness of Cdk1 signaling to antiapoptotic Bcl-2 proteins and sought here to test this hypothesis. Although the functions of many proteins can be explored by knockdown approaches, such a strategy is not feasible for Cdk1 because of its essential function in cell cycling and mitotic progression (12,13,24,25).…”

Section: Discussionmentioning

confidence: 99%

“…The existence of significant cross-talk between these pathways raises the possibility that the choice between mitotic death and mitotic slippage may depend on the net effect of one pathway on the other, that is, on the robustness of Cdk1/cyclin B1 signaling to Bcl-2 proteins. However, direct approaches to test this hypothesis are limited because it is difficult to interrogate Cdk1 function via elimination or long term inhibition without perturbing mitotic entry or exit, processes that depend on Cdk1 activation and inactivation, respectively (12,13).…”

mentioning

confidence: 99%

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Cyclin-dependent Kinase-1 (Cdk1)/Cyclin B1 Dictates Cell Fate after Mitotic Arrest via Phosphoregulation of Antiapoptotic Bcl-2 Proteins

Sakurikar

Eichhorn

Chambers

2012

Journal of Biological Chemistry

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Background: The molecular basis of variable cell fate after mitotic arrest is poorly understood. Results: The robustness of Cdk1 signaling to antiapoptotic Bcl-2 proteins dictates mitotic death versus mitotic slippage. Conclusion: Sustained Cdk1 activity coordinately promotes mitotic arrest and mitotic death. Significance: Defining the molecular basis of antimitotic drug action is important for their rational use clinically.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cyclin-dependent Kinase-1 (Cdk1)/Cyclin B1 Dictates Cell Fate after Mitotic Arrest via Phosphoregulation of Antiapoptotic Bcl-2 Proteins

Sakurikar

Eichhorn

Chambers

2012

Journal of Biological Chemistry

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“…Normal mitotic exit is triggered by the loss of CDK1 activity (42), therefore, we took advantage of the specific CDK1 inhibitor RO3306 (43) to induce a highly synchronized mitotic exit (Fig. 1A).…”

Section: Establishment Of a Synchronized Phosphatase Dependentmentioning

confidence: 99%

Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs

McCloy

Parker

Rogers

et al. 2015

Molecular & Cellular Proteomics

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Entry into mitosis is driven by the coordinated phosphorylation of thousands of proteins. For the cell to complete mitosis and divide into two identical daughter cells it must regulate dephosphorylation of these proteins in a highly ordered, temporal manner. There is currently a lack of a complete understanding of the phosphorylation changes that occur during the initial stages of mitotic exit in human cells. Therefore, we performed a large unbiased, global analysis to map the very first dephosphorylation events that occur as cells exit mitosis. We identified and quantified the modification of >16,000 phosphosites on >3300 unique proteins during early mitotic exit, providing up to eightfold greater resolution than previous studies. The data have been deposited to the ProteomeXchange with identifier PXD001559. Only a small fraction (ϳ10%) of phosphorylation sites were dephosphorylated during early mitotic exit and these occurred on proteins involved in critical early exit events, including organization of the mitotic spindle, the spindle assembly checkpoint, and reformation of the nuclear envelope. Surprisingly this enrichment was observed across all kinase consensus motifs, indicating that it is independent of the upstream phosphorylating kinase. Therefore, dephosphorylation of these sites is likely determined by the specificity of phosphatase/s rather than the activity of kinase/s. Dephosphorylation was significantly affected by the amino acids at and surrounding the phosphorylation site, with several unique evolutionarily conserved amino acids correlating strongly with phosphorylation status. These data provide a potential mechanism for the specificity of phosphatases, and how they co-ordinate the ordered events of mitotic exit. In summary, our results provide a global overview of the phosphorylation changes that occur during the very first stages of mitotic exit, providing novel mechanistic insight into how phosphatase/s specifically regulate this critical transition. Molecular & Cellular

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“…This steady rise in mitotic CDK activity helps establish the order of events during early mitosis, with a lower threshold of Clb-CDK activity triggering entry into mitosis and a second, higher one triggering entry into anaphase. Finally, once anaphase entry has been initiated, Clb proteolysis causes a decline in Clb-CDK activity, triggering exit from mitosis (during which thresholds may also play a role) (Wolf et al 2007). Interestingly, increasing amounts of mitotic CDK activity may also govern progression through early stages of mitosis in mammalian cells.…”

Section: A Model For How the Rise In Cdk Activity During Early Mitosimentioning

confidence: 99%

Mitotic CDKs control the metaphase–anaphase transition and trigger spindle elongation

Rahal¹,

Amon²

2008

Genes Dev.

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Mitotic cyclin-dependent kinases (CDKs) control entry into mitosis, but their role during mitotic progression is less well understood. Here we characterize the functions of CDK activity associated with the mitotic cyclins Clb1, Clb2, and Clb3. We show that Clb-CDKs are important for the activation of the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C)-Cdc20 that triggers the metaphase-anaphase transition. Furthermore, we define an essential role for Clb-CDK activity in anaphase spindle elongation. Thus, mitotic CDKs serve not only to initiate M phase, but are also needed continuously throughout mitosis to trigger key mitotic events such as APC/C activation and anaphase spindle elongation.[Keywords: APC/C; CDK; Cdc20; spindle elongation; mitosis] Supplemental material is available at http://www.genesdev.org.

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‘… The End of the Beginning’: Cdk1 Thresholds and Exit from Mitosis

Cited by 42 publications

References 39 publications

Cyclin-dependent Kinase-1 (Cdk1)/Cyclin B1 Dictates Cell Fate after Mitotic Arrest via Phosphoregulation of Antiapoptotic Bcl-2 Proteins

Cyclin-dependent Kinase-1 (Cdk1)/Cyclin B1 Dictates Cell Fate after Mitotic Arrest via Phosphoregulation of Antiapoptotic Bcl-2 Proteins

Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs

Mitotic CDKs control the metaphase–anaphase transition and trigger spindle elongation

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